Cattle nematodes resistant to macrocyclic lactones: comparative effects of P-glycoprotein modulation on the efficacy and disposition kinetics of ivermectin and moxidectin.

The role of the drug efflux pump, known as P-glycoprotein, in the pharmacokinetic disposition (host) and resistance mechanisms (target parasites) of the macrocyclic lactone (ML) antiparasitic compounds has been demonstrated. To achieve a deeper comprehension on the relationship between their pharmacokinetic and pharmacodynamic behaviors, the aim of the current work was to assess the comparative effect of loperamide, a well-established P-glycoprotein modulator, on the ivermectin and moxidectin disposition kinetics and efficacy against resistant nematodes in cattle. Fifty (50) Aberdeen Angus male calves were divided into five (5) experimental groups. Group A remained as an untreated control. Animals in the other experimental Groups received ivermectin (Group B) and moxidectin (Group C) (200 microg/kg, subcutaneously) given alone or co-administered with loperamide (0.4 mg/kg, three times every 24 h) (Groups D and E). Blood samples were collected over 30 days post-treatment and drug plasma concentrations were measured by HPLC with fluorescence detection. Estimation of the anthelmintic efficacy for the different drug treatments was performed by the faecal egg count reduction test (FECRT). Nematode larvae were identified by pooled faecal cultures for each experimental group. Cooperia spp. and Ostertagia spp. were the largely predominant nematode larvae in pre-treatment cultures. A low nematodicidal efficacy (measured by the FECRT) was observed for both ivermectin (23%) and moxidectin (69%) in cattle, which agrees with a high degree of resistance to both molecules. Cooperia spp. was the most abundant nematode species recovered after the different drug treatments. The egg output reduction values increased from 23% to 50% (ivermectin) and from 69% to 87% (moxidectin) following their co-administration with loperamide. Enhanced systemic concentrations and an altered disposition of both ML in cattle, which correlates with a tendency to increased anthelmintic efficacy, were observed in the presence of loperamide. Overall, the in vivo modulation of P-glycoprotein activity modified the kinetic behavior and improved the efficacy of the ML against resistant nematodes in cattle. The work provides further evidence on the high degree of resistance to ML in cattle nematodes and, shows for the first time under field conditions, that modulation of P-glycoprotein may be a valid pharmacological approach to improve the activity and extend the lifespan of these antiparasitic molecules.

Epidemiology and effects of gastrointestinal nematode infection on milk productions of dairy ewes.

66 Pampinta breed ewes were studied during milking to evaluate the infection and the effect of gastrointestinal nematode on milk production sheep system. Naturally infected ewes on pasture were randomly allocated to two groups: TG, suppressively treated group every four weeks with levamisole and UG, untreated group. Faecal nematode egg counts and larval differentiation were conducted monthly. Successive groups of worm free tracer lambs were grazed with ewes and then slaughtered for worm counts. Test-day milk yield of individual ewes was recorded and ewe machine-milking period length (MPL) were estimated. Faecal egg counts and tracer nematode numbers increased towards midsummer and declined sharply toward the end of the study. TG (188.0 +/- 60 liters) produced more (p < 0.066) milk liters than UG (171.9 +/- 52.2) and TG had significantly more extended (p < 0.041) MPL than those of UG. The present study showed that dairy sheep were negatively affected by worms, even when exposed to short periods of high acute nematode (mainly Haemonchus contortus) infection.

Anthelmintic resistance in cattle nematode in the western Pampeana Region of Argentina.

During the past three years there have been several reports of cattle anthelmintic resistance (AR) in Argentina. Twenty-five cattle herds in the west fattening area of the Pampeana Region were surveyed to assess the prevalence of AR and the species of nematode involved. The survey involved fattening and cow-calf systems with a mean of 6760 bovines. Resistance was determined in vivo by a faecal egg count reduction test (FECRT). Efficacies from the World Association for the Advancement of Veterinary Parasitology (WAAVP) formula were compared with those obtained from the Abbott formula. Sixty 6-12-month-old calves were selected from each property and divided into four groups, namely, IVM (ivermectin, 0.2mg/kg), BZD (fenbendazole, 5mg/kg or albendazole 7.5mg/kg), LVM (levamisole, 7.5mg/kg) and Control (untreated group). Nematode larvae were identified by four pooled faecal cultures for each group. Cooperia and Ostertagia were the predominant nematode larvae in pre-treatment cultures. The mean FECRT efficacies for IVM, BZD and LVM were 81.0+/-21%, 93.3+/-8% and 97.6+/-4%, respectively. AR was detected in 16 (64%) herds. IVM resistance was present in 15 herds and BZD resistance in eight herds (32%). Resistance to both ivermectin and fenbendazole was present in seven herds. LVM resistance was not detected. Cooperia was the predominant post-treatment nematode in all the herds with IVM resistance. In one herd with IVM resistance, Ostertagia counts were slightly increased over pretreatment counts. Ostertagia was the prevalent post-treatment genera in herds with BZD resistance. A high level of resistance to ivermectin was recorded in this fattening region of Argentina. Also several herds with resistance to benzimidazole were observed. These results show the importance of AR in Argentinian cattle production. High correlation between WAAVP and Abbott formulae was observed. However, under some uncertain diagnosis, both formulae could be applied as complementary to help result interpretations.